Validation of a single-pass surgical trajectory to enable AAV2-hAADC infusion into brainstem and mid-brain in nonhuman primate

验证单次手术轨迹，使 AAV2-hAADC 能够输注到非人灵长类动物的脑干和中脑

• 批准号: 10040048
• 负责人: Krystof S Bankiewicz
• 金额: $ 42.9万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10040048
• 关键词: 3-Dimensional; Ablation; Acids; Adverse effects; Adverse event; Affect; Amino Acids; Annual Reports; Area; Awareness; Basal Ganglia; Bilateral; Biochemical; Brain; Brain Diseases; Brain Stem; Cannulas; Carboxy-Lyases; Caregivers; Cell Nucleus; Child; Childhood; Chronic; Clinical; Clinical Research; Clinical Trials; Cohort Analysis; DOPA decarboxylase; Data; Deficiency Diseases; Deposition; Disease; Dopamine; Dopamine Agonists; Dyskinetic syndrome; Dystonia; Emotional; Enzymes; Evaluation; Gene Delivery; Gene Expression; Genes; Genetic Diseases; Goals; Homovanillic Acid; Human; Hydroxyindoleacetic Acid; Hypokinesia; Impaired cognition; Impairment; Infusion procedures; Inherited; Intervention; Levodopa; Life; Limbic System; Medical; Midbrain structure; Muscle hypotonia; Mutation; Neurologic; Neurologic Symptoms; Neurotransmitters; Norepinephrine; Operative Surgical Procedures; Outcome Study; Pathologic; Pathway interactions; Patients; Procedures; Protocols documentation; Public Health; Research; Safety; Serious Adverse Event; Serotonin; Site; Sleep disturbances; Societies; Structure; Substantia nigra structure; Symptoms; System; Testing; Therapeutic; Time; Treatment Efficacy; Validation; Ventral Tegmental Area; Viral Vector; Writing; aromatic L-amino acid decarboxylase deficiency; base; burden of illness; cohort; cost; dorsal raphe nucleus; experimental study; gene therapy; improved; loss of function mutation; monoamine; motor symptom; nervous system disorder; nonhuman primate; noradrenergic; pars compacta; programs; recessive genetic trait; recruit; vector

PROJECT SUMMARY/ABSTRACT Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare pediatric genetic disorder in which mutations in the DOPA decarboxylase gene (DDC) result in a non-functional AADC enzyme that causes the ablation of dopamine and serotonin synthesis. Affected children suffer prominent motor symptoms, including hypokinesia, hypotonia, oculogyric crises and dystonia, as well as emotional lability, sleep disturbance and cognitive impairment. Patients derive little symptomatic benefit from currently available medical therapies. Our long-term goal is to provide a therapeutic approach to eliminate the neurological signs and symptoms of the disease by increasing the AADC levels via localized infusion of a viral vector (AAV2) encoding human AADC into affected nuclei in the brain. In our current exploratory clinical study (NCT02852213), we have treated 9 patients with AADC deficiency with a single bilateral infusion into the pre-nigral region to restore normal dopamine synthesis in the basal ganglia and limbic system. Preliminary evaluations from cohorts 1 and 2 have proven this approach to be safe with only mild and transient dyskinesia about one month and a half after surgery. Marked reduction or elimination of oculogyric crises has been observed. Biochemical analyses showed an increase in dopamine metabolite homovanillic acid (HVA), a slight reduction of 3-oxymethyldopa (3-OMD) while serotonin metabolite 5-hydroxyindolacetic acid (5-HIAA) remained unchanged in all patients. Currently, analyses of these cohorts, 24 and 12 months after surgery respectively, also showed that there have been no adverse events or serious adverse events related to the surgical procedure or the vector. The present proposal seeks to accumulate safety data in nonhuman primates in which a single cannula pass will enable vector delivery into serotonergic and noradrenergic nuclei as well as the current dopaminergic nuclei. Data from this study will be used to submit a new IND and recruit more patients for this new procedure. In our view, the proposed research will have a significant impact on public health. Although AADC deficiency is a rare pediatric disease, the burden to caregivers and the cost to society is large over the life of the patients not to mention the plight of the patients themselves. In the larger sense, projects like this will continue to enhance our ability to treat inherited neurological diseases.

项目总结/摘要 芳香族L-氨基酸脱羧酶（AADC）缺乏症是一种罕见的儿科遗传性疾病， DOPA脱羧酶基因（DDC）中的突变导致非功能性AADC酶， 多巴胺和血清素的合成受影响的儿童会出现明显的运动症状，包括运动功能减退， 张力减退、眼球转动危象和肌张力障碍，以及情绪不稳定、睡眠障碍和认知障碍 损伤患者从目前可用的药物治疗中获得的症状益处很少。我们的长期 目的是提供一种治疗方法，以消除神经体征和症状的疾病， 通过将编码人AADC的病毒载体（AAV 2）局部输注到受影响的细胞中来增加AADC水平， 大脑中的核团。在我们目前的探索性临床研究（NCT 02852213）中，我们治疗了9例患者， AADC缺乏，单次双侧输注至黑质前区以恢复正常多巴胺合成 基底神经节和边缘系统队列1和队列2的初步评价证明了这一点 这种方法是安全的，只有轻微的和短暂的运动障碍约一个半月后手术。标记 已经观察到眼球转动危象的减少或消除。生化分析显示， 多巴胺代谢产物高香草酸（HVA），3-羟甲基多巴（3-OMD）轻微减少，而血清素 代谢产物5-羟基吲哚乙酸（5-HIAA）在所有患者中保持不变。目前，这些分析 分别在术后24个月和12个月的队列也显示没有不良事件或 与外科手术或载体相关的严重不良事件。 本提案旨在积累非人灵长类动物的安全性数据，其中单次插管通过将 能够将载体递送到肾上腺素能和去甲肾上腺素能核以及当前的多巴胺能核中。 本研究的数据将用于提交新的IND，并招募更多患者用于这项新手术。 我们认为，拟议的研究将对公共卫生产生重大影响。虽然AADC缺陷是 作为一种罕见的儿科疾病，护理人员的负担和社会成本在患者的一生中都很大， 提到病人自身的困境从更大的意义上说，像这样的项目将继续增强 我们治疗遗传性神经疾病的能力。